THE INFLUENCE OF METHOD OF ADMINISTRATION AND COVARIATES ON THE PHARMACOKINETICS OF PROPOFOL IN ADULT VOLUNTEERS

Background: Unresolved issues with propofol include whether the pharma cokinetics are linear with dose, are influenced by method of administr ation (bolus vs. infusion), or are influenced by age. Recently, a new formulation of propofol emulsion, containing disodium edetate (EDTA), was introduced in the United States. Addition of EDTA was found by the manufacturer to significantly reduce bacterial growth. This study inv estigated the influences of method of administration, infusion rate, p atient covariates, and EDTA on the pharmacokinetics of propofol. Metho ds: Twenty-four healthy volunteers aged 26-81 yr were given a bolus do se of propofol, followed 1 h later by a 60-min infusion. Each voluntee r was randomly assigned to an infusion rate of 25, 50, 100, or 200 mu g.kg(-1).min(-1). Each volunteer was studied tn ice under otherwise id entical circumstances: once receiving propofol without EDTA and once r eceiving propofol with EDTA. The influence of the method of administra tion and of the volunteer covariates was explored by fitting a three-c ompartment mamillary model to the data. The influence of EDTA was inve stigated by direct comparison of the measured concentrations in both s essions. Results: The concentrations of propofol with and without EDTA mere not significantly different. The concentration measurements afte r the bolus dose were significantly underpredicted by the parameters o btained just from the infusion data. The kinetics of propofol were lin ear within the infusion range of 25-200 mu g.kg(-1).min(-1). Age was a significant covariate for Volume(2) and Clearance(2), as were weight, height, and lean body mass for the metabolic clearance. Conclusions: These results demonstrate that method of administration (bolus vs. inf usion), but not EDTA, influences the pharmacokinetics of propofol. Wit hin the clinically relevant range, the kinetics of propofol during inf usions are linear regarding infusion rate.